ABCG2 Polymorphism Markedly Affects the Pharmacokinetics of Atorvastatin and Rosuvastatin

Abstract

The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P < or = 0.01). In MDCKII-ABCG2 cells, atorvastatin transport was increased in the apical direction as compared with vector control cells (transport ratio 1.9 +/- 0.1 vs. 1.1 +/- 0.1). These results indicate that the ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and, even more so, of rosuvastatin-potentially affecting the efficacy and toxicity of statin therapy.

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

“…The effects of these two polymorphisms on atorvastatin pharmacokinetics have been robustly identified in Caucasian populations [14,15] and were also recently illustrated in Japanese subjects [16]. It can be hypothesised that the lack of effect in the current work may be due to the small sample size and the complete absence of homozygous variant individuals with respect to these SNPs (Table 2).…”

“…For the purpose of this work, all studied participants were retrospectively genotyped for 18 genetic polymorphisms located in 7 different genes. More specifically 3, 3, 1, 1, 7, 2 and 1 polymorphisms were genotyped in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively, as previous literature suggests that all these genes might be implicated in atorvastatin disposition [14,15,[22][23][24][25][26]. The distribution of these variants in the studied population is reported in Table 2.…”

“…In a different study [15] a polymorphism (c.421C>A or rs2231142) in the gene coding for the BCRP efflux transporter (ABCG2) was reported to be associated with 72% increased ATA exposure in homozygous variant individuals (AA) compared to wild-type individuals (CC). The increased ATA exposure in the polymorphic subjects has been suggested to occur due to decreased efflux on the intestinal wall and subsequently higher bioavailability after oral administration.…”

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

“…Active uptake into hepatocytes is facilitated by multiple organic anion transporting polypeptide (OATP) isoforms; sodium-taurocholate cotransporting polypeptide also has been reported to play a role (Ho et al, 2006;Abe et al, 2008;Kitamura et al, 2008). MRP2 and BCRP are the canalicular proteins primarily responsible for RSV biliary excretion (Huang et al, 2006;Kitamura et al, 2008;Keskitalo et al, 2009;Jemnitz et al, 2010;Hobbs et al, 2012). The role of basolateral transport proteins in RSV efflux from hepatocytes back into sinusoidal blood has not been examined.…”

“…The role of basolateral transport proteins in RSV efflux from hepatocytes back into sinusoidal blood has not been examined. Hepatic basolateral efflux of RSV could be clinically relevant because impaired hepatic transport resulting from drug-drug interactions and genetic polymorphisms has been shown to alter the pharmacokinetics of RSV Simonson et al, 2004;Zhang et al, 2006;Kiser et al, 2008;Kitamura et al, 2008;Keskitalo et al, 2009;Hobbs et al, 2012). Some of these changes have been associated with altered efficacy (i.e., lowering of low-density lipoprotein) of RSV (Simonson et al, 2003;Tomlinson et al, 2010), and increased systemic exposure has been associated with life-threatening rhabdomyolysis, which is related to statin use in general (Hamilton-Craig, 2001; Thompson et al, 2003).…”